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This Article Full Text Full Text (PDF) All Versions of this Article: 288/6/H2925    most recent 01202.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (13) Citing Articles via Google Scholar Google Scholar Articles by Ennis, I. L. Articles by Cingolani, H. E. Search for Related Content PubMed PubMed Citation Articles by Ennis, I. L. Articles by Cingolani, H. E.

Endothelin isoforms and the response to myocardial stretch

Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Argentina

Submitted 1 December 2004 ; accepted in final form 26 January 2005

Myocardial stretch elicits a biphasic increase in developed force with a first rapid force response and a second slow force response (SFR). The rapid phase is due to an increase in myofilament Ca²⁺ responsiveness; the SFR, analyzed here, is ascribed to a progressive increase in Ca²⁺ transients. Experiments were performed in cat papillary muscles to further elucidate the signaling pathway underlying the SFR. Although the SFR was diminished by BQ-123, a similar endothelin (ET)-1-induced increase in force was not affected: 23 ± 2 vs. 23 ± 3% (not significant). Instead, BQ-123 suppressed the contractile effects of ET-2 or ET-3 (21 ± 2 and 25 ± 3% vs. –1 ± 1 and –7 ± 3% respectively, P < 0.05), suggesting that ET-2 or ET-3, but not ET-1, was involved in the SFR. Each isoform activated the Na⁺/H⁺ exchanger (NHE-1), increasing intracellular Na⁺ concentration by 2.0 ± 0.1, 2.3 ± 0.1, and 2.1 ± 0.4 mmol/l for ET-1, ET-2, and ET-3, respectively (P < 0.05). The NHE-1 inhibitor HOE-642 prevented the increases in force and intracellular Na⁺ concentration induced by all the ET isoforms, but only ET-2 and ET-3 effects were sensitive to BQ-123. Real-time RT-PCR measurements of prepro-ET-1, -ET-2, and -ET-3 were performed before and 5, 15, and 30 min after stretch. No changes in ET-1 or ET-2, but an increase of 60% in ET-3, mRNA after 15 min of stretch were detected. Stretch-induced ET-3 mRNA upregulation and its mechanical counterpart were suppressed by AT₁ receptor blockade with losartan. These data suggest a role for AT₁-mediated ET-3 released in the early activation of NHE-1 that follows myocardial stretch.

myocardial contractility; signal transduction; endothelin isoforms; sodium/hydrogen exchanger-1

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